The in vivo activation of cyclophosphamide (Endoxan) to cytostatic and alkylating metabolites has been studied. Endoxan is metabolized to the weak anion by microsomal dealkylation in the rat's liver; this product is the first alkylating metabolite. About 80% of the alkylating activity of the serum, occurring 30 min after injection of Endoxan is presented by this primary alkylating metabolite. Nor‐N‐mustard and N‐2‐chloroethyl‐aziridine were found only in traces. Although some activation was detected in the liver, the lungs and to a minor extent the kidneys, this phenomenon has not been detected in the screened experimental rat tumors. The authors conclude that the greater specificity of Endoxan as compared to other cytostatic agents of the N‐mustard group may be due to some specific permeation properties of the primary alkylating metabolite of Endoxan rather than to a possible specific mechanism of action of this compound within tumor cells.
The activated metabolites of ifosfamide and cyclophosphamide (4-hydroxy-ifosfamide and 4-hydroxy-cyclophosphamide) were analysed fluorometrically by condensation of liberated acrolein with m-aminophenol yielding 7-hydroxyguinoline. Interfering fluorescence of blood and urine was eliminated by extraction with dichlormethane and determination of blanks in which the liberated acrolein reacted with hydrazine to non-fluorescent pyrazoline. The modified test proved effective in identifying low levels of activated metabolites in man. After i.v. injection of 20 mg/kg cyclophosphamide or ifosfamide peak levels of activated cyclophosphamide (4.7 nmol/ml) and the area under the curve (c.t = 16.7 nmol.ml/h) showed mean values three times higher than those found for activated ifosfamide. One per cent of the applied dosis of cyclophosphamide vs. 0.3% of ifosfamide was excreted as activated metabolites. Due to the high stability of activated cyclophosphamide and ifosfamide in urine a low liberation rate of acrolein was found, the concentration of which in urine was below 0.5 nmol/ml. Acrolein, which was directly liberated from activated cyclophosphamide or ifosfamide, does not seem to play an important role in the urotoxicity of these cytostatics.
The authors studied the alkylating activity in the blood serum of man and rats after administration of cyclophosphamide, and its dependence on dosage. The alkylating activity was determined by means of the NBP test. For the process of activation, distribution in the body, and elimination, a mathematic model was developed and checked by means of the experimental data. The following results were obtained: 1. The cyclophosphamide activation curves studied for the doses of 15.6, 31.3, and 62.5 mg/kg are very constant in the rat, the NBP regression lines depending clearly on dosage. 2. The pharmacokietics of the metabolite level in man, studied for the doses of 30 and 60 mg/kg, show great individual fluctuations. But even here the dependence of the activity curves on dosage is statistically significant. 3. The average peaks of the metabolite level in man, related to the same dose, are about half to three quarters those found in the rat. 4. In man, the alkylating activity in the blood is detectable longer than in the rat. The values of the elimination constants in man are about two thirds of those in the rat. 5. Direct determination of the cyclophosphamide activation rate in liver sections of man and rats shows the activation rate in man related to the moist weight of the liver, to be‐even in vitro‐only about 60% of that of the rat. 6. Our findings show that there are no basic qualitative differences in cyclophosphamide activation between man and rat. They offer interesting aspects for the improvement of the therapeutic use of cyclophosphamide.
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